May 2013 Blog with Durk and Sandy

Appetizers

Can't act, slightly bald, also dances.
— RKO Pictures screen test, comments about Fred Astaire

I suppose a knighthood is out of the question now?
— Spike Milligan, in a fax to Prince Charles after he called him a “little groveling bastard.”

A thing moderately good is not so good as it ought to be. Moderation in temper is always a virtue; but moderation in principle is always a vice.
— Thomas Paine, Common Sense

It is hard to imagine a more stupid or more dangerous way of making decisions than by putting those decisions in the hands of people who pay no price for being wrong.
— Thomas Sowell

You can't possibly hear the last movement of Beethoven’s Seventh and go slow.
— Oscar Levant, explaining his way out of a speeding ticket

The Sleeping Brain Decides What to Remember and What to Forget

A new paper¹ describes the sleep-dependent memory-processing factory that decides what to do with all that information you encountered during the day. As the paper’s authors point out, only some of that information is consolidated so as to become a part of a long-term knowledge base. The paper sifts through evidence from studies of naps, sleep deprivation, correlations of sleep stages and memory processing, sleep physiology, regional brain activity measured during and after sleep with PET and fMRI studies, cellular firing patterns, and synaptic and intracellular measures of plasticity to conclude that there is convincing evidence of sleep processing of memory with improvement of the overall knowledge base.

The authors discuss the new understanding that not all information is uniformly preserved, but that there is an exquisite selection process of memories underway during sleep. For example, they report that emotional memories can be selectively consolidated, especially during rapid eye-movement (REM) sleep. It has also been found that memories can be selectively maintained when they contain information on potential monetary rewards. Interestingly, when subjects of sleep memory studies have been told that they would be tested on certain areas of information and not on others provided before sleep, they were found after sleep to have retained more of the information they were told they would be tested on. Hence, the brain “knew” what to do to recall the relevant information.

Moreover, the authors explain, it is possible for the brain to generate new information during the processing of the memory-derived information. “Whether consolidation necessarily precedes these integrative processes (serial processing) is not yet known, but no clear cases of integration without consolidation have been observed. We use the term ‘memory evolution’ to reflect both the qualitative changes that can occur during such integrative processing and the extended time course over which they occur.”¹ In gist extraction, the authors refer to the identification of commonalities between items in a collection of memories even when individual item memories are forgotten. Some studies have been found to show that during sleep subjects can extract overarching rules that govern recently studied sets of information, such that understanding of relationships between the sets is improved following sleep.

One study reported by the authors dealt with subjects taught a rote method for solving a class of mathematical problems for which there was a shortcut solution (about which subjects were not told). After a night of post-training sleep, however, subjects were found to be 2.6 times more likely to discover this shortcut than after an equal period of time awake (59.1 versus 22.7% of subjects).¹ But, interestingly, even those who did not discover the shortcut benefitted from sleep by improving the speed with which they were able to perform the rote method of solving the problems. Those who became faster without discovering the shortcut improved their speed (using the rote method) three times more than either those who discovered the shortcut or those who remained awake.

This study examines important sleep processes at a systems level rather than at a neurotransmitter level. Understanding sleep involves comprehending its mechanisms from the micro-level details (neuro­transmitters and synapses) to the overarching system architecture. For more about the neurotransmitter level, see our article describing how our SleepScape formula works here: (www.life-enhancement.com/magazine/ article/2807-introducing-sleepscape) and the first of its ingredients (glycine) here:(www.life-enhancement.com/ magazine/article/2813-ingredients-in-sleepscape) , the second of its ingredients (GABA) here: (www.life-enhancement.com/magazine/article/2836-ingredients-in- sleepscape)

Life Enhancement magazine and Durk Pearson & Sandy Shaw’s Life Extension Newsletter therein have been providing details on SleepScape’s ingredients, continuing this month on page 17 with choline (a precursor to the neurotransmitter acetylcholine).

Reference

1. Stickgold and Walker. Sleep-dependent memory triage: evolving generalization through selective processing. Nat Neurosci. 16(2):139-45 (2013).

Hydrogen Gas Protects Beagle Dog Hearts from 
Ischemia-Reperfusion Injury-Induced Infarction

Researchers investigated a possible mechanism to explain how the inhalation of hydrogen gas following ischemia-reperfusion injury in rat hearts limits the infarct size.¹Noting that the effect of hydrogen on such heart injury in large animals has not been studied, they focused their study on beagle dogs that had the left anterior descending coronary artery occluded for 90 minutes, followed by reperfusion for 6 hours. The animals were treated with either 1.3% hydrogen or control gas (70% nitrogen and 30% oxygen) ten minutes prior to reperfusion until 1 hour of reperfusion had taken place.

The area of killed heart cells (infarct) was reduced by hydrogen gas as compared to control gas (and normalized by risk area) 20.6 ± 2.8% vs. 44.0 ± 2%; p<0.001. (In other words, the area at risk due to the occlusion following by reperfusion was reduced by 20.6 ± 2.8% by the hydrogen gas treatment as compared to 44.0 ± 2% by the control gas treatment.) They also identified the opening of mitochondrial K-ATP channels followed by inhibition of the mitochondrial permeability transition pores as accompanying the protective effects of limiting ischemia-reperfusion-induced infarct. The authors note that “recent accumulated evidence regarding cardioprotection afforded by ischemic pre- or post-conditioning has culminated in the idea that opening of mitochondrial ATP-sensitive K+ channels followed by inhibition of mitochondrial permeability transition pores plays a central role in limiting infarct size.”¹

The researchers used drugs that prevent the opening of the mitochondrial K-ATP channel as a way to test whether the protective effects of hydrogen gas was mediated by the opening of these channels. The administration of either of two such drugs abolished the infarct size-limiting effect of hydrogen gas.

The researchers also observed that inhalation of hydrogen gas tended to reduce the incidence of lethal ventricular arrhythmia, although they did not investigate the mechanisms responsible for that.

Reference

1. Yoshida et al. H2 mediates cardioprotection via involvements of K-ATP channels and permeability transition pores of mitochondria in dogs. Cardiovasc Drugs Ther. 26:217-226 (2012).

Important Advance in Cancer Treatment: 
Restoring Activity of Tumor Suppressor Genes 
No FDA Approval Required!

A very recent paper¹ reports the exciting news that curcumin, a yellow pigment derived from the curry spice turmeric, has been shown to reactivate several hyper­methyl­ated (turned off) tumor suppressor genes in lung, colon, prostate, and breast cancer cells. One of the most common causes of cancer is loss of one or more key tumor suppressor genes, which can occur as a result of mutation, but also by another process, DNA hyper­methyl­ation.

Too little DNA methylation (hypomethylation) can result in the activation of oncogenes that promote cancer, whereas excessive DNA methylation (hypermethylation) can silence tumor suppressor genes that would otherwise inhibit the development of cancer. When tumor suppressor genes are hypermethylated, they are prevented from being expressed. Unlike mutations, however, DNA hypermethyl­ation can be reversed by dietary methylation inhibitors for chemoprevention and also chemotherapy.¹

A new paper¹ now reveals in vitro and in vivo evidence in mice that curcumin can reactivate the tumor suppressor gene RASSF1A in breast cancer cells, resulting in significant activity against tumor growth. Another paper² reports that “RASSF1A methylation has the potential to be an ideal cancer biomarker as it occurs at moderate to high frequency in a very wide range of tumour types, yet is comparatively rarely found in normal tissues.” The same paper² also reports that “RASSF1A promoter methyl­ation has been demonstrated in epithelial hyperplasia and intraductal papillomas of the breast, as well as cancerous epithelium, suggesting that RASSF1A methylation is an early event in breast tumourigenesis.” RASSF1A methyl­ation has also been suggested to be an early event in thyroid tumouri­genesis, childhood neoplasia, and endometrial carcino­genesis.² In lung cancer, RASSF1A methylation as a diagnostic marker has been investigated and found to occur in ~34% of NSCLC (non-small cell lung cancer) tumors, accompanied by methylation in the corresponding serum.²

Another paper³ describes curcumin as a “potent DNA hypomethylation agent” and explains how the authors understand curcumin to restore the activity of deactivated tumor suppressor genes. The authors of this paper³ note that two nucleoside analogs (azanucleosides) with hypomethylating activity (decitabine or 5-azacytidine) have been approved by the FDA for the treatment of myelodysplastic syndrome, but that, although the results are encouraging, these drugs can be very toxic (by suppressing bone marrow). Curcumin, on the other hand, has been shown to be well tolerated in three different phase 1 clinical trials of up to 12 grams a day.^3B The authors³ found that curcumin and one of its major metabolites, tetrahydrocurcumin, are effective in inhibiting hypermethylation induced by DNMT1 (a DNA methyltransferase). Using a leukemia cell line, the global DNA methylation of MV4-11 cells remained unchanged at 1.0 μM curcumin, but decreased about 15–20% at 3.0 and 30.0 μM curcumin compared to the untreated basal methylation level of the cell line.

A paper⁴ with the same lead author as paper #3 who is also the last author of paper #1 reports that the sesquiterpene lactone parthenolide, the principal bioactive sesquiterpene lactone of the herb feverfew, reactivated the tumor suppressor gene HIN-1 by inhibiting DNA methyltransferase 1 (DNMT1) and thus is an agent of DNA hypomethylation.

Finally, an earlier paper⁵ reported that EGCG, a major polyphenol in green tea, was effective in inhibiting DNA methyltransferase and reactivating methylation-silenced tumor suppressor genes in cancer cell lines.

What these results suggest is that cancer prevention could be enhanced, perhaps very significantly, by taking hypomethylation agents such as these in safe doses and that their use (possibly together with standard chemotherapy, which is often effective in cancer patients that do not have silenced tumor suppressor genes) could markedly improve chances of survival for these patients who, in the absence of reactivating their silenced tumor suppressor genes may have a dismal prognosis.

Another advantage of using safe natural products for the treatment of cancer is that, provided no claims are made for their efficacy in the treatment of cancer, they do not have to receive FDA approval for sale in the marketplace and, hence, do not require a doctor’s prescription and are generally relatively inexpensive. However, that makes you responsible for your own health in a really major way, so be sure to work with a knowledgeable physician if you choose to use these substances to treat your cancer, as there may be very little in the way of clinical data on their use (correct dosages are usually difficult to predict from animal studies). There is nothing that can replace a physician with a lot of experience, who follows the natural products scientific literature, and who has good diagnostic skills. Also avoid, as much as possible, doctors who are tied up in knots by bureaucratic political rules and regulations (e.g., Medicare, Medicaid, Obama­care) that may (though they may not want to admit it even to themselves) make it impossible for them to use their best judgment in treating their patients.

A new paper⁶ reports that the gene (CRYAA) critical for the maintenance of eye lens transparency can be repressed by hypermethylation in age-related cataract, the leading cause of blindness among older adults. The paper mentions DNA methylation inhibitor drugs, zebularine and 5-Aza-C as possible treatments, but refers to complications related to their toxicity, though mentioning that zebularine has much lower toxicity than 5-Aza-C. However, we refer to the above description of nutritional hypomethylating agents that are almost certainly to be far lower in toxicity. Apparently, these natural substances have not yet been tried as treatments for age-related cataract or we would have expected to see this mentioned in the paper. We hope to see such research soon, though we note that these natural substances cannot be patented and, hence, are unlikely to receive research funding by pharmaceutical companies. In fact, Big Pharma has heretofore been likely to use its huge political lobbying machine to prevent competition by natural products, in part by engaging the FDA on their behalf.

If dietary supplement companies could make truthful claims concerning their effects on cataracts (let alone in the treatment of cancer), we would see substantial money invested by dietary supplement companies to establish data to support truthful health claims for diseases. If you can’t tell people about the results of your research, what's the point of doing it? The FDA’s censorship of truthful information results in the suffering and, in the case of cancer, premature deaths of large numbers of Americans. Incredibly, most Americans believe the Big Lie that the FDA protects people from the lies of dietary supplement companies who will supposedly say anything to sell you their pills when, as we see it, the FDA’s suppression of truthful health claims are causing far more harm. No system can entirely eliminate false claims, but the current one is throwing out most truthful claims (and freedom of speech along with it) in order to eliminate false claims. Unfortunately, most of what is published in major media as “news” on health claims largely parrot back what is contained in FDA press releases.

References

1. Du et al. Reactivation of RASSF1A in breast cancer cells by curcumin. Nutr Cancer.64(8):1228-35 (2012). 
2. van der Weyden and Adams. The Ras-association domain family (RASSF) members and their role in human tumourigenesis. Biochim Biophys Acta. 1776(1):58-85 (2007). 
3. Liu et al. Curcumin is a potent DNA hypomethylation agent. Bioorg Med Chem Lett.19:706-9 (2009). 
3B. Anand et al. Bioavailability of curcumin: problems and promises. Mol Pharm.4(6):807-18 (2007). 
4. Liu et al. Modulation of DNA methylation by a sesquiterpene lactone parthenolide. J Pharmacol Exp Ther. 329(2):505-14 (2009). 
5. Fang et al. Tea polyphenol (-)-epigallocatechin-3-gallate inhibits DNA methyltransferase and reactivates methylation-silenced genes in cancer cell lines. Cancer Res. 63:7563-70 (2003).

Stuck in an Apathetic Rut? Cholinesterase Inhibition 
Ameliorates Apathy and Loss of Motivational Drive in Mice

Scientists studying neural mechanisms for apathetic behavior report1 that a cholinesterase inhibitor (phenserine was used in this study) reversed many of the signs of apathy in male C57BL/6 mice) subject to chronic restraint stress. As the authors explain, apathy shares some overlapping features with depression, but is not the same. Apathy “can be distinguished [from depression] by lack of dysphoric symptoms including sadness, hopelessness and guilt.”¹ Instead, apathetic animals exhibit extreme withdrawal of involvement and a paucity of emotion, a state characterized by a lack of motivation in relation to goal-oriented and self-initiated activity.

The authors wanted to test whether facilitating the cholinergic system could ameliorate the apathetic state induced by chronic restraint stress. It is not clear why they used the particular cholinesterase inhibitor (phenserine) that they did, but it is interesting to note that the final author of the paper (who is usually the scientist who runs the lab where the work is done) is listed as a paid employee of Johnson & Johnson Pharmaceutical Research under “Competing Interests” at the end of the paper. This MAY (just a speculation on our part) indicate that the cholinesterase inhibitor is a product of Johnson & Johnson Pharmaceutical Research.

Several features of the apathetic behavior exhibited by the control animals were ameliorated in the experimental animals treated with the cholinesterase inhibitor. “Overall, CRS [chronic restraint stress]-exposed mice displayed significant decreases in exploratory behavior such as rear-up and sniff, as well as in locomotor behaviors including walk slowly, remain low, and hang cuddled for several hours directly prior to the onset of the dark cycle and before the onset of the light cycle, suggesting a decrease in initiation of non-essential activities. However, directly prior to dark cycle onset, inactive behaviors such as twitch and rest increased in the CRS mice.”¹ The researchers observed accumulation of deltaFosB in the MS/vDB, said to be one of the major basal forebrain cholinergic nuclei, suggesting that this area had undergone significant changes in gene expression as a result of CRS.

The authors note that two other papers reported that the cholinesterase inhibitors galantamine and donepezil lead to increased dopamine release in the NAcc (nucleus accumbens), an area associated with motivation and reward and speculate that the behavioral effects of phenserine in this paper may have resulted from activating cholinergic interneurons in brain areas associated with motivation and reward.

Reference

1. Martinowich et al. Acetylcholinesterase inhibition ameliorates deficits in motivational drive. Behav Brain Funct. 8:15 (2012)

Powerful Punch of Evidence-Supported 
Aromatherapy: Menthol Protects Against Beta 
Amyloid Peptide Induced Cognitive Deficits in Mice

A surprising new paper¹ reports that menthol, a constituent of essential oils (e.g., peppermint and other mint oils) that have been used since the time of ancient Egypt and are now considered part of the aromatherapy wing of alternative medicine, provided significant protection in aged and beta-amyloid protein-treated mice against cognitive decline. Sniff, baby, sniff!

One particularly nice thing about menthol is that it is readily available, safe and inexpensive, and easy to use. In fact, menthol (frequently in combination with eucalyptus, camphor, and thymol) is a commonly used and effective bronchodilator that, unlike bronchodilator drugs such as beta-adrenergic agonists, does not cause cardiac arrhythmias or other adverse reactions.

The researchers reported that menthol administered successively for 10 days significantly increased the amount of time spent in the target quadrant of the dreaded Morris water maze in young mice, thus showing improved spatial learning and memory. Moreover, “pre-treatment with menthol reversed the amnesia induced in animals upon treatment with beta-amyloid on 10th day.” Menthol improved working memory in both aged and young mice, with the potentiation of working memory more profound with 100 mg/kg s.c. menthol. Other studies were cited in which menthol exhibited anticholinesterase inhibitory activity and increased intracellular ATP in nerve cells (which the researchers proposed may have an inhibitory effect on ATP gated potassium channels).

Beta-amyloid peptide treatment administered to young mice on day 7 reduced glutathione content (increased oxidative stress).

Pretreatment with menthol showed a significant increase in glutathione content, reversing the increased oxidative stress seen in the animals not pretreated with menthol.

“Higher dose of menthol also improves the brain function through decrease in malondialdehyde level [lipid peroxidation product] in aged and beta-amyloid treated mice. Lower dose of menthol (100 mg/kg s.c.) showed improvement in spatial working memory as compared to higher dose.”¹

One easy way to use menthol is to buy it as a spray, spray a couple of spritzes into a Kleenex^® tissue, then hold over your nose and breathe deeply a few times.

Whether enough menthol can be obtained by inhalation of its vapor was not determined by this experiment since it was administered by subcutaneous injection. Never­theless, peppermint oil can certainly be taken orally, though we recommend diluting it with a vegetable cooking oil to prevent irritation. Note that menthol delivered by either peppermint hard candy or smoking (though we do not recommend smoking to obtain menthol) is directly absorbed by the oral and nasal mucosa and efficiently transported to the brain.

Reference

1. Bhadania et al. Protective effect of menthol on beta-amyloid peptide induced cognitive deficits in mice. Eur J Pharmacol. 681:50-4 (2012).

A delicious, nutritious fun smoothie—you will need:

• 8–10 ounces milk
• two or three handfuls of fresh or frozen blueberries (frozen are great because they help chill your smoothie); fresh or frozen strawberries are great, too 
• 40–60 grams (4–6 tablespoons) of whey protein 
• two to three tablespoons of natural cocoa (NOT dutched—dutching destroys much of the healthful polyphenols) 
• two tablespoons of erythritol 
• 1⁄2 tsp. vanilla 

Plus (as desired):

• 1 tablespoon Hydrogen Power™ (prebiotic for hydrogen producing gut microbes)
• 1⁄2 tsp. taurine (tasteless) 
• 1⁄2 tsp. trehalose (adds no taste) 
• 1⁄2 tsp. glutamine (adds no taste) 
• 1 tsp. Memory Upgrade III™ (contains 1 gram choline) 
• 1 tbsp. InnerPower Plus™ (contains 6 g. arginine)

Also, if desired, add 1⁄4 cup ice cream. You can add more, but remember there is a lot of fat and calories in the ice cream.

Process for about 25 seconds until blended. Enjoy!

We drink one of these smoothies nearly every morning and sometimes have one again in the afternoon. Durk also adds a single serving of the French Roast Bold coffee by Starbucks to his (only in the morning).